The Multiple Sclerosis Emerging Therapies Collaborative includes the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), the MS Coalition, the American Academy of Neurology, and the VA Multiple Sclerosis Centers of Excellence East and West.

Indicated for the treatment of pseudobulbar affect (PBA), which is defined by involuntary, sudden, and frequent episodes of laughing and/or crying that are generally out of proportion or inappropriate to the situation.

Studies to support the effectiveness of DM/QS were performed in patients with underlying amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). Although DM/QS has not been shown to be safe or effective in other types of emotional lability that can commonly occur – for example, in Alzheimer's disease and other dementias – DM/QS is approved for treatment of PBA regardless of the underlying medical condition.

Use is not approved for other types of emotional lability.

Use is not restricted to any particular disease course of MS.

Safety and effectiveness in patients under 18 years of age have not been established.

What were the findings in the pivotal trials of this medication?

Approval was based on efficacy and safety data from four phase 3 trials and additional, uncontrolled studies of PBA. Relevant published trials include Brooks et al. (Neurology 2004;63:1364-1370), Panitch et al. (Ann Neurology 2006;59:780-787), and Pioro et al. (Ann Neurol 2010;68:693-702). Only the Pioro et al study (discussed below) included subjects who received the currently approved fixed-dose combination.

Trial Design: One phase 3, 12-week, placebo-controlled, double-blind trial randomized 326 patients with either MS (40%) or ALS (60%) to treatment with DM 30 mg/QS 10mg, DM 20 mg/QS 10 mg, or placebo (1:1:1). All subjects had a baseline score of ≥ 13 on the Center for Neurologic Studies - Lability Scale (CNS-LS) and were 18–80 years of age. ALS was diagnosed within the previous 30 months by the El Escorial criteria, and MS or probable MS was diagnosed by 2001 McDonald criteria. Patients took the medication or placebo once daily for the first week and twice daily for the remaining weeks of the trial.

Primary Endpoint: Change in the daily number of episodes of PBA from baseline as recorded in the patient's diary at either dose of DM/QS when compared with placebo.

The primary outcome measure, laughing and crying episodes, was significantly lower for patients on both fixed doses of DM/QS as compared with those on placebo (46.9% and 49.0%, respectively, for the higher and lower DM formulations).

Mean CNS-LS scores decreased 8.2 points for both the higher and lower DM formulations as compared with 5.7 points for those on placebo.

When compared with the placebo group, both the higher- and lower-dose treatment groups were about 60% more likely to experience a complete remission of PBA episodes during the last 2 weeks of treatment.

What is the mechanism of action and the rationale for its use in MS?

The exact mechanism of action for the effect of DM/QS on PBA is unknown.

DM is a dextrorotatory analogue of levorphanol. It is a σ-1 receptor agonist as well as a noncompetitive inhibitor of the excitatory NMDA receptor. Blocking σ-1 receptors inhibits glutamate release and, along with the noncompetitive inhibition of the NMDA glutamate receptor, would lead to an inhibition of excitatory synaptic transmission. It is not clear how that leads to inhibition of PBA symptoms.

There is a theory that PBA is caused by abnormalities of cortical-pontine-cerebellar pathways that involve glutaminergic transmission (Miller et al, 2011).

What is the delivery route and recommended dosing?

DM 20 mg/QS 10 mg as one capsule taken once per day for 7 days, then one capsule taken every 12 hours thereafter.

Capsules should be taken whole, without having been broken or crushed.

Can this medication be used with other medications?

Disease-modifying Therapies (DMT):

DM/QS was used along with interferon-β or glatiramer acetate by some patients with MS participating in the Panitch et al 2006 study. No altered tolerance of the combination was reported.

There are no published data on experiences with other FDA-approved DMTs such as natalizumab or fingolimod.

Given that fingolimod can induce bradycardia and first-degree heart block, and given that QS can increase the QT interval, caution when combining these agents is advised.

Other Medications:

DM/QS should not be used with other medications containing quinidine, quinine, or mefloquine. These include a number of nonprescription, over-the counter medications containing either DM or quinidine or similar medications.

DM/QS should not be used in patients taking monoamine oxidase inhibitors (MAOIs), and use with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants may increase the risk of serotonin syndrome.

QS is a potent inhibitor of cytochrome P450 2D6 and should not be used with other medications that prolong the QT interval and are metabolized by CYP2D6, including thioridazine and pimozide.

DM/QS should be used with caution with any medications that can prolong the QT interval and inhibit CYP3A4, particularly in patients with cardiac disease.

How does the expected treatment effect compare with the treatment effect provided by other available medications?

No direct comparisons have been made of DM/QS with any other medications used to treat PBA. Although there have been studies reporting success in treating PBA with other agents, including low doses of amitriptyline, there are no other FDA-approved medications for the treatment of PBA.

What are the possible short-term side effects? What is the range of severity of side effects, and what are the recommended management strategies?

In combined studies at different test doses, side effects that were seen in >3% of patients and at an incidence of >2 times the rate seen in the placebo group in shortterm trials included diarrhea, dizziness, vomiting, asthenia, peripheral edema, urinary tract infections, increased gamma-glutamyltransferase, and flatulence.

In one study that included patients with MS and patients with ALS, dizziness, nausea, diarrhea, and urinary tract infections were more frequent in the DM 30 mg/QS 10 mg group but not in the DM 20 mg/QS 10 mg group as compared with the placebo group. In the study limited to patients with MS, dizziness was more common in patients treated with DM 30 mg/QS 30 mg, but there was no statistical difference relative to placebo-treated patients for any other side effect.

Immune-mediated thrombocytopenia can be caused by quinidine and can range from mild to severe, even leading to death. Nonspecific symptoms—including lightheadedness, chills, fever, nausea, and vomiting—can occur and can precede the evidence of thrombocytopenia. DM/QS should be stopped immediately if the patient experiences the above symptoms while on treatment. Thrombocytopenia may clear spontaneously in a few days, but careful monitoring is required. Cross reaction occurs with structurally related agents, including quinine and mefloquine. Re-challenge should not be attempted, as a more rapid and severe thrombocytopenia may occur.

QS has been associated with a lupus-like syndrome with positive antinuclear antibodies, although not in the studies with DM/QS. Other side effects of QS—including rash, lymphadenopathy, vasculitis, uveitis, hemolytic anemia, bronchospasm, angioedema, agranulocytosis, sicca complex, myalgias, elevation of serum levels of muscle enzymes, and pneumonitis—have been reported, although not in studies of DM/QS.

QS has been associated with hepatitis, including granulomatous hepatitis, generally in the first 2 weeks of therapy. The infection may be accompanied by fever and thrombocytopenia. Treatment consists of withdrawal of the medication. This side effect was not seen in the short-term studies in the neurologic patients treated with DM/QS.

Cardiac effects are well reported with QS, including dose-dependent QTc prolongation, and can lead to torsades de pointes-type ventricular tachycardia. Patients at risk of developing prolonged QTc or torsades de pointes-type ventricular tachycardia should have a baseline ECG performed, followed by a repeat ECG 3–4 hours after the first dose. Risk factors include diagnosis of cardiac disease with leftventricular hypertrophy or dysfunction, use of medications known to prolong the QT interval or to be strong or moderate CYP3A inhibitors (including atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, and verapamil), or consumption of grapefruit juice.

Reevalution should be done if symptoms suggestive of cardiac disease occur, bradycardia medications that prolong QT are added, or hypokalemia and hypomagnesemia occur.

Serotonin syndrome can occur if this medication is combined with tricyclic or SSRI antidepressants. Patients in studies were not taking any of these agents during the study period.

Anticholinergic effects of QS could theoretically cause problems in myasthenia gravis or other diseases that are adversely affected by anticholinergic agents.

What are the known long-range (morbidity and mortality) health risks?

DM has potential for abuse, although abuse was not observed in these relatively short-term studies. Abuse and drug seeking with DM have been more frequent in adolescents.

As noted there are multiple known risks in the use of QS, including thrombocytopenia and cardiac effects.

Has the FDA included any black box warnings about this medication?

There are no black box warnings for DM/QS.

What training is recommended or required for clinicians or patients before initiating this treatment?

No specific training is required for clinicians or patients.

What is the pregnancy rating for this medication, and what is known about possible carcinogenesis, mutagenesis, and impairment of fertility?

This medication is classified as Category C. There are no well-controlled studies of DM/QS in pregnant women. DM/QS was shown to be teratogenic and to increase intrauterine death when given to pregnant animals.

DM/QS should only be used during pregnancy when potential benefits justify the risk to the fetus, particularly since this is not a disease-modifying therapy.

There are no data on excretion of DM or QS in breast milk, so risks associated with breastfeeding are not known.

DM and QS have no known effects on carcinogenesis, mutagenesis, or fertility.

Does this medication interact or interfere with oral contraceptives?

There is no known interaction or interference with oral contraceptives.

DM/QS should not be used by patients with a prior history of hypersensitivity to DM, quinidine, quinine, or mefloquine, or who have had quinidine-induced thrombocytopenia, hepatitis, bone marrow depression, or lupus-like syndrome.

DM/QS should not be used in patients with a prolonged QT interval, congenital long QT syndrome, a history suggestive of torsades de pointes, or heart failure.

DM/QS should not be used in patients receiving MAOIs or in patients who have taken MAOIs within the preceding 14 days.

DM/QS should not be taken by patients receiving medications that both prolong QT interval and are metabolized by CYP2D6, such as thioridazine and pimozide.

DM/QS should not be given to patients with complete AV block without implanted pacemakers or who are at a high risk of complete AV block.

No routine blood tests are required or suggested prior to starting treatment or during therapy with DM/QS, but ECG should be performed. Repeat ECG should be performed if a patient develops a risk factor for prolonged QT interval or AV block.

Close monitoring should be done in patients who are taking antidepressants (SSRIs or tricyclics), digoxin, or CYP2D6 inhibitors, or in patients who develop electrolyte imbalance or hypomagnesaemia.

There are no data on use in pediatric patients. While patients over 65 years of age were included in the studies of DM/QS, the numbers were small; therefore, it is not known if patients over 65 years of age respond differently than younger patients.

There have been no problems with the use of DM/QS in patients with mild to moderate renal or hepatic dysfunction; there are no data on patients with severe renal or hepatic dysfunction.

Are there any recommended limits on treatment duration with this medication?

There are no recommended limits on duration of treatment with this medication.

What happens following termination of treatment with this medication?

DM/QS can be discontinued at any time. PBA symptoms would be expected to persist or return after discontinuation of the medication.

What treatment options are available for patients who have been treated with DM/QS?

There are no other FDA-approved medications to decrease occurrence of PBA episodes. There are studies demonstrating some benefit with the use of low doses of amitriptyline.

What is the washout period?

When DM 30 mg/QS 30 mg is administered to individuals with normal CYP2D6 function, the half-life of DM is approximately 13 hours and of QS approximately 7 hours. No information is available regarding the half-life of the approved dose.

How can a provider identify a suboptimal treatment response?

There are no firm criteria for determining a suboptimal response. It will be necessary to work with the patient and family to see whether there is a decrease in PBA episodes.

A small percentage of individuals have a mutation in the gene for CYP2D6 that prevents QS or any other CYP2D6 inhibitors from blocking this enzyme function. When the mutation is present DM is rapidly metabolized, and DM/QS does not have a therapeutic effect on PBA.

Is the manufacturer/distributor offering any financial assistance program for patients?

DM/QS can be used by patients with any clinical MS type (relapsing-remitting, secondary progressive, primary progressive, progressive relapsing) for the indication of symptomatic management of PBA.

COMMENTARY BY AUTHORS

Appropriate patient selection is extremely important when prescribing this medication and monitoring its outcome. It may be helpful to include both the patient and family during the initial encounter, to educate them on use of the medication, and during follow-up visits, to determine response to therapy. Baseline estimates and follow-up notes or communication documenting responses are advised for continued use of a medication that may not benefit all patients with PBA.

Although not explicitly required, establishment of a baseline ECG seems prudent prior to starting treatment with DM/QS. Establishment of a baseline CBC, BUN/ creatinine, LFTs, electrolytes, and magnesium should also be considered, particularly if there are reasons to suspect abnormalities.

Many patients with MS have depression and/or anxiety and are using antidepressants. The combination of these medications with DM/QS could be problematic.

The combined use of DM/QS (which can cause prolonged QT interval) and fingolimod (the initial dose of which can cause various degrees of heart block and bradycardia) should be undertaken with great caution.

Because patients with MS may be taking a number of prescribed or over-the-counter medications, it is essential to obtain a complete medication profile before this medication is started.

The Emerging Therapies Collaborative is proud to be a source of information about multiple sclerosis. Our comments are based on published data and expert opinion, but do not represent individual therapeutic recommendations or prescriptions. For specific information and advice, consult your physician.